David Spade's parents divorced when he was a toddler, and his father would "pop in once a year to take us to the circus," Spade says. In grade school, he says he was taunted relentlessly by the other kids. His mother eventually remarried, but Spade's stepfather killed himself in 1980, when Spade was 15. At about this time, perhaps as a defense mechanism, young Spade began taking almost nothing seriously, and became known as a class cut-up. His high school hijinks included planting stink bombs, and raising underwear up the flagpole. During his senior year in high school, he was suspended for the seemingly minor crime of putting up unauthorized "Class of 82 rocks" posters in the hallways.

He started doing stand-up comedy while attending college, and made his big-screen debut in 1987's Police Academy 4: Citizens on Patrol. He performed stand-up on Fox's The Late Show with Joan Rivers, and when she was fired, Fox asked Spade to be one of several rotating hosts, but he declined. After a few more years languishing in night clubs, Spade joined the cast of Saturday Night Live in 1990, where his caricatures included a hostile receptionist for Dick Clark, and a hostile celebrity reporter insulting the stars in "Hollywood Minute". After six seasons on SNL, Spade went on to star as a sarcastic office worker on the sitcom Just Shoot Me with Laura San Giacomo, and eventually wandered into the cast of 8 Simple Rules after the untimely death of its star, John Ritter. He briefly hosted The Showbiz Show, a talk show on Comedy Central.

In the cartoon The Emperor's New Groove, Spade voiced the Emperor, "a bumptious, cynical, totally selfish egomaniac". He has also starred in several low-budget and low-grossing comedies, including Tommy Boy with longtime partner Chris Farley, Joe Dirt with Dennis Miller, and Dickie Roberts: Former Child Star with Doris Roberts

In 2000, he was attacked and robbed by his personal assistant, one David "Skippy" Malloy. In 2001, he was ticketed and prosecuted for reckless jet-skiing.